Evidence suggests that two major factors predisposing individuals to initiate and maintain substance abuse are abnormal responses to rewards and punishments and impaired ability to inhibit prepotent responses. These factors may act, in part, through synaptic pathology in the ventral striatum, amygdala, frontal cortex and related """"""""motivation"""""""" circuitry to predispose vulnerable individuals to persistent substance abuse. From a cognitive/behavioral neuroscience perspective, evidence supports the first part of this vulnerability as being expressed, in part, as general impairments in the normal ability to engage motivational circuitry by delayed rewards and punishments, biasing individuals toward immediate rewards (exemplified by cocaine), and impulsive behaviors. A specific part of this vulnerability is hypothesized to involve problems in the brain circuitry for reward and punishment expectation - a """"""""Reward Deficit Hypothesis."""""""" The second aspect of vulnerability is hypothesized to involve a diminished ability to inhibit prepotent responses and thus act impulsively. Little prior research has examined the relationship between these two factors at a behavioral or brain level in healthy controls or substance abusers. We will study 80 per group of adult subjects (50% male) who either are currently cocaine dependent, formerly cocaine dependent but currently abstinent or matched controls. The 240 subjects will be characterized on scales and interviews assessing aspects of impulsivity and several computer tasks measuring behavioral impulsivity: (delay discounting, risk/reward decision-making, inhibition of prepotent response), and also assessed on potential covariates including psychopathy/antisocial personality, ADHD and lifetime substance use. With functional MRI we will use two distinct but complementary behavioral tasks to examine reward deficit and a third to examine response inhibition, to dissect the underlying functional anatomy of the relevant circuits. The first two tasks quantify responses in motivational circuitry to situations involving both expectation of and receipt of rewards and punishments and the propensity to take risks on one of the tasks, The paradigms are a Monetary Incentive Delay Task that assesses anticipation of reward and punishment, separating anticipatory (motivational) from outcome (consummatory) components of reward processing. The other, the Domino Task involves decision making under conditions of uncertainty, anticipation to outcome, response to outcome, risk taking behavior, and a social interaction context. The response inhibition task is a Go/No Go paradigm. Subjective responses evinced during task performance will be quantified as important dependent measures. We will separate out effects of recent versus past chronic cocaine use on task-related brain activation patterns. Overall, we thus plan to elucidate the inter-relationship between two important substance abuse-related factors at both a behavioral and a neural circuit level.
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